Morpholinylpyridone compounds

ABSTRACT

The invention provides novel morpholinylpyridone compounds of formula (I), pharmaceutical compositions containing such compounds, and methods for using such compounds in treatment of diseases including cancer, type II diabetes, inflammatory diseases, autoimmune diseases, neurodegenerative disorders, cardiovascular disorders and viral infections; Formula (I) wherein R 1 , R 2  and A are as defined in the specification.

FIELD OF THE INVENTION

The invention provides novel morpholinylpyridone compounds of formula(I), pharmaceutical compositions containing such compounds, and methodsfor using such compounds in treatment of diseases including cancer andtype II diabetes.

BACKGROUND OF THE INVENTION

Enzymes belonging to the family of phosphatidylinositide 3-kinases(PI3K) are regulators of several important cellular events. The familyconsists of three classes, I, II and III and while the Class I group hasbeen an interesting drug target for many years, Class II and III areless exploited. The PI3K Class III, vacuolar protein sorting 34 (Vps34,PIK3C3) forms a heterodimer with its regulatory subunit p150 (Vps15) andthis dimer takes part in several complexes regulating vesiculartrafficking events such as autophagy, endocytosis, exocytosis andmicropinocytosis (Amaravadi et al. Clin Cancer Res. 2011, 17:654-666;Carpentier et al. 2013, Traffic). The enzyme is responsible forphosphorylation of phosphatidylinositol (PI) to phosphatidylinositol(3)-phosphate (PI3P). The ligand binding to PX and FYVE domains resultsin recruiting and delocalization of these effector proteins that lead tovesicular formation, elongation and movement (Backer et al. J Biochem.2008, 410:1-17).

Autophagy is a catabolic process where cellular components are targetedfor degradation by enclosing them in double-membrane vesicles,auto-phagosomes that are fused with the protease-containing lysosomes.This is a mean for the cell to handle damaged organelles and misfoldedproteins and by that maintain cellular function. The pathway is also away of recirculating cellular content into new building blocks (Boya etal, Nat Cell Biol 2013, 15; 713-720). Autophagy is a cellular responseto stressful conditions as nutrient deprivation, acidosis and hypoxiabut also to drug treatment.

Therefore, autophagy inhibition is a means to potentiate cancer drugsand resensitize drug resistant tumors (Nagelkerke et al, Semin CancerBiol 2014, 31; 99-105). Most advanced tumors show a high upregulation ofautophagic flux (Leone et al. Trends in Endocrin Metab 2013, 24;209-217). An established marker for studying autophagic flux is thedetection of autophagic puncta in the form of lipidated LC3 protein onthe autophagosome. Inhibition of Vps34 results in the inhibition ofautophagy as measured by LC3 redistribution into puncta (Dowdle et al.,Nat Cell Biol 2014, 16; 1069-79).

As recently described, ablation of the regulatory subunit p150 leads toincreased insulin sensitivity in vivo due to decreased insulin receptorinternalization (Nemazanyy, Nature Commun., 2015, 6:8283). A kinase deadheterozygous animal model confirms this result with increased glucosetolerance and increased insulin sensitivity (WO2013076501).

Several disease states could benefit from Vps34 inhibition includingcancer, inflammatory diseases, autoimmune diseases, neurodegenerativedisorders, cardiovascular disorders, type II diabetes and viralinfections (Reviewed in Rubinsztein et al, Nat Rev 2012, 11; 709-730).Cancer forms that would benefit from Vps34 inhibition include, but arenot limited to, breast cancer, such as triple negative breast cancer,bladder cancer, liver cancer, cervical cancer, pancreatic cancer,leukemia, lymphoma, renal cancer, colon cancer, glioma, prostate cancer,ovarian cancer, melanoma, and lung cancer as well as hypoxic tumors.There is thus a need for novel and potent inhibitors of Vps34.

Previous disclosures describing Vps34 inhibitors in use to affectdiseases include WO2015150555; WO2015150557; WO2015108861; WO2015108881;WO2012085815; WO2012085244; WO2013190510; Farkas, J. Biol. Chem., 2011286(45) 38904-12.

DESCRIPTION OF THE INVENTION

An object of the invention is to provide novel and potent inhibitors ofVps34. Another object of the invention is to provide novel and potentinhibitors of Vps34 that may be used for treating cancer and otherdiseases such as type II diabetes.

According to one aspect of the invention, there is provided a compoundof formula (I)

wherein

R¹ is C₁-C₃alkyl or cyclopropyl;

R² is selected from hydrogen, C₁-C₃haloalkyl and C₁-C₃alkyl;

A is

wherein

R³ is selected from R⁶, C₁-C₆alkyl, amino, N-C₁-C₃alkylamino,N,N-diC₁-C₃alkylamino and C₁-C₃alkoxyC₁-C₃alkyl, said C₁-C₆alkyl andsaid C₁-C₃alkoxyC₁-C₃alkyl being optionally substituted with one R⁶and/or one or more halo;

R⁴ is selected from C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl,C₃-C₆cycloalkyl and phenyl, said phenyl being optionally andindependently substituted with one of more of fluoro, chloro, methyl,methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl, cyclopropyl;

R⁵ is selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy, C₁-C₆haloalkyl andC₃-C₆cycloalkyl;

R⁶ is selected from phenyl, monocyclic heteroaryl, C₃-C₆cycloalkyl,heterocyclyl, each optionally substituted with one or more R⁷;

R⁷ is selected from halogen, amino, N-C₁-C₃alkylamino,N,N-diC₁-C₃alkylamino and C₁-C₃alkoxyC₁-C₃alkyl, C₁-C₃alkoxy,C₁-C₃haloalkoxy, C₃-C₆cycloalkyl, C₁-C₃haloalkyl and C₁-C₃alkyl;

or a pharmaceutically acceptable salt thereof.

According to one embodiment of this aspect of the invention, R² isselected from hydrogen and C₁-C₃alkyl, such as hydrogen.

According to one embodiment of this aspect of the invention, R¹ ismethyl.

According to one embodiment of this aspect of the invention, R⁷ isselected from fluoro, cyclopropyl and methyl.

According to one embodiment of this aspect of the invention, R⁷ isfluoro or methyl.

According to one embodiment of this aspect of the invention, R⁴ isselected from methyl, trifluoromethyl, cyclopropyl and phenyl, saidphenyl being optionally meta-substituted with one of fluoro, chloro,methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl andcyclopropyl; and R⁵ is selected from chloro, cyclopropyl, methyl andtrifluoromethyl.

According to one embodiment of this aspect of the invention, R⁴ and R⁵are independently selected from C₁-C₃haloalkyl, such asC₁-C₃fluorooalkyl, such as trifluoromethyl.

According to one embodiment of this aspect of the invention, R⁴ isselected from methyl, trifluoromethyl and cyclopropyl; and

R⁵ is selected from chloro, cyclopropyl, methyl and trifluoromethyl.

According to one embodiment of this aspect of the invention, R³ isselected from R⁶, C₁-C₃alkyl, N,N-diC₁-C₃alkylamino andmethoxyC₁-C₃alkyl, said C₁-C₃alkyl being optionally substituted with oneR⁶.

According to one embodiment of this aspect of the invention, R⁶ isselected from phenyl, pyridyl, morpholinyl, imidazolyl, isoxazolyl,pyrazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl andtetrahydrofuryl, each optionally substituted with one or more R⁷.

According to one embodiment of this aspect of the invention, R⁶ isselected from phenyl, pyridyl, morpholinyl, imidazolyl, pyrazolyl,cyclopropyl, pyrrolidinyl, piperidinyl, and tetrahydrofuryl, eachoptionally substituted with one or more R⁷

According to one embodiment of this aspect of the invention, R⁶ isselected from phenyl, pyridyl, pyrrolidinyl, pyrazolyl, tetrahydrofuryl,each optionally substituted with one or more R⁷.

According to one embodiment of this aspect of the invention, R⁶ isselected from

According to one embodiment of this aspect of the invention, R⁶ isselected from

According to one embodiment of this aspect of the invention, R⁶ isselected from

According to one embodiment of this aspect of the invention, R³ isselected from

According to one embodiment of this aspect of the invention, R³ isselected from

According to one embodiment of this aspect of the invention, R³ isselected from

According to one embodiment of this aspect of the invention, A is

According to one embodiment of this aspect of the invention, A is

According to one embodiment of this aspect of the invention, R¹ ismethyl or cyclopropyl;

R² is hydrogen;

A is

and R³ is selected from

According to one embodiment of this aspect of the invention, R¹ ismethyl;

R² is hydrogen;

R⁴ and R⁵ are CF₃;

A is

and R³ is selected from

According to one embodiment of this aspect of the invention, R¹ ismethyl;

R² is hydrogen;

R⁴ is CF₃;

A is

and R³ is selected from

According to one embodiment of this aspect of the invention,

R¹ is methyl or cyclopropyl;

R² is hydrogen;

R⁴ and R⁵ are CF₃;

A is

and R³ is selected from

According to one embodiment of this aspect of the invention, saidcompound is4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide;

6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

6-[4-Cyclopropylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-(1-piperidylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-morpholinosulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

6-[4-(1,2-Dimethylimidazol-4-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

6-[4-(1-methylcyclopropyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;

N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)benzenesulfonamide;

or a pharmaceutically acceptable salt thereof.

According to one embodiment of this aspect of the invention, saidcompound is

4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide;

6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;

4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;

or pharmaceutically acceptable salt thereof.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in the treatment or prophylaxis of adisease.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating cancer. Typically, saidcancer is selected from breast cancer, such as triple negative breastcancer, bladder cancer, liver cancer, cervical cancer, pancreaticcancer, leukemia, lymphoma, renal cancer, colon cancer, glioma, prostatecancer, ovarian cancer, melanoma and lung cancer, as well as hypoxictumors.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating type II diabetes.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating a disease selected frominflammatory diseases, autoimmune diseases, neurodegenerative disorders,cardiovascular disorders and viral infections.

In one aspect of the invention, there is provided use of a compoundaccording to the present invention, in the preparation of a medicamentfor treating cancer. Typically said cancer is selected from breastcancer, such as triple negative breast cancer, bladder cancer, livercancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, renalcancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanomaand lung cancer, as well as hypoxic tumors.

In one aspect of the invention, there is provided use of a compoundaccording to the present invention, in the preparation of a medicamentfor treating type II diabetes.

In one aspect of the invention, there is provided use of a compoundaccording to the present invention, in the preparation of a medicamentfor treating a disease selected from inflammatory diseases, autoimmunediseases, neurodegenerative disorders, cardiovascular disorders andviral infections.

In one aspect of the invention, there is provided a method of treatingcancer, comprising administering a therapeutically effective amount of acompound according to the present invention, to a patient in needthereof. Typically, said cancer is selected from breast cancer, such astriple negative breast cancer, bladder cancer, liver cancer, cervicalcancer, pancreatic cancer, leukemia, lymphoma, renal cancer, coloncancer, glioma, prostate cancer, ovarian cancer, melanoma and lungcancer, as well as hypoxic tumors.

In one aspect of the invention, there is provided a compound accordingto the present invention, for use in treating cancer, wherein saidcancer treatment further comprises radiation therapy.

In one aspect of the invention, there is provided a method of treatingcancer, comprising administering a therapeutically effective amount of acompound according to the present invention, to a patient in needthereof, in conjunction with radiation therapy.

The compounds of the present invention may also be employed in cancertreatment in conjunction with radiation therapy and/or surgicalintervention. Generally, the use of cytotoxic and/or cytostatic agentsin combination with a compound or composition of the present inventionwill serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemotherapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

In one aspect of the invention, there is provided a method of treatingtype II diabetes, comprising administering a therapeutically effectiveamount of a compound according to the present invention, to a patient inneed thereof.

In one aspect of the invention, there is provided a method of treatinghypoxic tumors, comprising administering a therapeutically effectiveamount of a compound according to the present invention, to a patient inneed thereof.

In one aspect of the invention, there is provided a method of treating adisease selected from inflammatory diseases, autoimmune diseases,neurodegenerative disorders, and viral infections, comprisingadministering a therapeutically effective amount of a compound accordingto the present invention, to a patient in need thereof.

In one aspect of the invention, there is provided a pharmaceuticalcomposition comprising a compound according to the present invention,and a pharmaceutically acceptable diluent, carrier and/or excipient.

In one aspect of the invention, there is provided a pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to claim 1 and another anticancer agent selected fromalkylating agents, antimetabolites, anticancer camptothecin derivatives,plant-derived anticancer agents, antibiotics, enzymes, platinumcoordination complexes, tyrosine kinase inhibitors, hormones, hormoneantagonists, monoclonal antibodies, interferons, and biological responsemodifiers.

As used herein, the term “C₁-C₆alkyl” means both linear and branchedchain saturated hydrocarbon groups with 1 to 6 carbon atoms. Examples ofC₁-C₆alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, t-butyl, n-pentyl, 4-methyl-butyl, n-hexyl,2-ethyl-butyl groups. Among unbranched C₁-C₆alkyl groups, typical onesare methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl groups. Amongbranched alkyl groups, there may be mentioned iso-propyl, iso-butyl,sec-butyl, t-butyl, 4-methyl-butyl and 2-ethyl-butyl groups.

As used herein, the term “C₁-C₃alkyl” means both linear and branchedchain saturated hydrocarbon groups with 1 to 3 carbon atoms. Examples ofC₁-C₃alkyl groups include methyl, ethyl, n-propyl and isopropyl groups.

As used herein, the term “C₁-C₆alkoxy” means the group O-C₁-C₆alkyl,where “C₁-C₆alkyl” is used as described above. Examples of C₁-C₆alkoxygroups include, but are not limited to, methoxy, ethoxy, isopropoxy,n-propoxy, n-butoxy, n-hexoxy, 3-methyl-butoxy groups.

As used herein, the term “C₁-C₃alkoxy” means the group O-C₁-C₃alkyl,where “C₁-C₃alkyl” is used as described above. Examples of C₁-C₃alkoxygroups include, but are not limited to, methoxy, ethoxy, isopropoxy andn-propoxy.

As used herein, the term “C₁-C₆haloalkyl” means both linear and branchedchain saturated hydrocarbon groups, with 1 to 6 carbon atoms and with 1to all hydrogens substituted by a halogen of different or same type.Examples of C₁-C₆haloalkyl groups include methyl substituted with 1 to 3halogen atoms, ethyl substituted with 1 to 5 halogen atoms, n-propyl oriso-propyl substituted with 1 to 7 halogen atoms, n-butyl or iso-butylsubstituted with 1 to 9 halogen atoms, and sec-butyl or t-butyl groupssubstituted with 1 to 9 halogen atoms.

As used herein, the term “C₁-C₃haloalkyl” means both linear and branchedchain saturated hydrocarbon groups, with 1 to 3 carbon atoms and with 1to all hydrogens substituted by a halogen of different or same type.Examples of C₁-C₃haloalkyl groups include methyl substituted with 1 to 3halogen atoms, ethyl substituted with 1 to 5 halogen atoms, and n-propylor iso-propyl substituted with 1 to 7 halogen atoms.

As used herein, the term “C₁-C₃haloalkoxy” means both linear andbranched chain saturated alkoxy groups, with 1 to 3 carbon atoms andwith 1 to all hydrogen atoms substituted by a halogen atom of differentor same type. Examples of C₁-C₃haloalkoxy groups include methoxysubstituted with 1 to 3 halogen atoms, ethoxy substituted with 1 to 5halogen atoms, and n-propoxy or iso-propoxy substituted with 1 to 7halogen atoms.

As used herein, the term “C₁-C₃fluoroalkyl” means both linear andbranched chain saturated hydrocarbon groups, with 1 to 3 carbon atomsand with 1 to all hydrogen atoms substituted by a fluorine atom.Examples of C₁-C₃fluoroalkyl groups include methyl substituted with 1 to3 fluorine atoms, ethyl substituted with 1 to 5 fluorine atoms, andn-propyl or iso-propyl substituted with 1 to 7 fluorine atoms.

As used herein, the term “C₁-C₃fluoroalkoxy” means both linear andbranched chain saturated alkoxy groups, with 1 to 3 carbon atoms andwith 1 to all hydrogen atoms substituted by a fluorine atom. Examples ofC₁-C₃fluoroalkoxy groups include methoxy substituted with 1 to 3fluorine atoms, ethoxy substituted with 1 to 5 fluorine atoms, andn-propoxy or iso-propoxy substituted with 1 to 7 fluorine atoms.

As used herein, the term “C₃-C₆cycloalkyl” means a cyclic saturatedhydrocarbon group, with 3 to 6 carbon atoms. Examples of C₃-C₆cycloalkylgroups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term “C₁-C₃alkoxyC₁-C₃alkyl” means a both linear andbranched chain saturated hydrocarbon group, with 1 to 3 carbon atoms,substituted with an alkoxy group with 1 to 3 carbon atoms. Examples ofC₁-C₃alkoxyC₁-C₃alkyl groups are drawn below.

As used herein, the term “C₁-C₃cyanoalkyl” means both a linear andbranched chain cyano (CN) derivative, with one to three carbon atomsincluding the carbon atom that is part of the cyano group. Examples ofC₁-C₃cyanoalkyl groups are drawn below.

As used herein, the term N-C₁-C₃alkylamino means an amino substituentcarrying one C₁-C₃alkyl group as defined supra. Examples ofN-C₁-C₃alkylamino are drawn below.

As used herein, the term N,N-diC₁-C₃alkylamino means an aminosubstituent carrying two C₁-C₃alkyl groups as defined supra. Examples ofN,N-diC₁-C₃alkylamino are drawn below.

As used herein, the term “halogen” means fluorine, chlorine, bromine oriodine. As used herein, the term “halo” means fluoro, chloro, bromo oriodo. It is to be understood that when a substituent is halo, it isalways bound to a carbon.

As used herein, the term “heteroaryl” means a monocyclic aromatic groupof carbon atoms wherein from one to three of the carbon atoms is/arereplaced by one or more heteroatoms independently selected fromnitrogen, oxygen or sulfur. In a bicyclic aryl, one of the rings may bepartially saturated.

As used herein, the term “monocyclic heteroaryl” means a monocyclicaromatic group of carbon atoms wherein from one to three of the carbonatoms is/are replaced by one or more heteroatoms independently selectedfrom nitrogen, oxygen or sulfur.

Examples of monocyclic heteroaryl groups include, but are not limitedto, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl,isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.

As used herein, the term “heterocyclyl” means a cyclic group of carbonatoms wherein from one to three of the carbon atoms is/are replaced byone or more heteroatoms independently selected from nitrogen, oxygen andsulfur. Examples of heterocyclyl groups include, but are not limited to,tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl and dioxanyl.

Depending on the substituents present in compounds of the formula (I),the compounds may form salts which are within the scope of the presentinvention. Salts of compounds of formula (I), which are suitable for usein medicine are those wherein a counterion is pharmaceuticallyacceptable.

Suitable salts according to the invention include those formed withorganic or inorganic acids or bases. In particular, suitable saltsformed with acids according to the invention include those formed withmineral acids, strong organic carboxylic acids, such as alkanecarboxylicacids of 1 to 4 carbon atoms which are unsubstituted or substituted, forexample, by halogen, such as saturated or unsaturated dicarboxylicacids, such as hydroxycarboxylic acids, such as amino acids, or withorganic sulfonic acids, such as (C₁-C₄)alkyl or aryl sulfonic acidswhich are unsubstituted or substituted, for example by halogen.Pharmaceutically acceptable acid addition salts include those formedfrom hydrochloric, hydrobromic, sulphuric, nitric, citric, tartaric,acetic, phosphoric, lactic, pyruvic, acetic, trifluoroacetic, succinic,perchloric, fumaric, maleic, glycolic, lactic, salicylic, oxaloacetic,methanesulfonic, ethanesulfonic, p-toluenesulfonic, formic, benzoic,malonic, naphthalene-2-sulfonic, benzenesulfonic, isethionic, ascorbic,malic, phthalic, aspartic, and glutamic acids, lysine and arginine.

Pharmaceutically acceptable base salts include ammonium salts, alkalimetal salts, for example those of potassium and sodium, alkaline earthmetal salts, for example those of calcium and magnesium, and salts withorganic bases, for example dicyclohexylamine, N-methyl-D-glucamine,morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di- or trilower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl,triethyl, tributyl or dimethylpropylamine, or a mono-, di- or trihydroxylower alkylamine, for example mono-, di- or triethanolamine.Corresponding internal salts may furthermore be formed.

The compounds of the invention may be used in the prophylaxis and/ortreatment as such, or in a form of a pharmaceutical composition. Whileit is possible for the active ingredient to be administered alone, it isalso possible for it to be present in a pharmaceutical composition.Accordingly, the invention provides a pharmaceutical compositioncomprising a compound of formula (I), and a pharmaceutically acceptablediluent, excipient and/or carrier. Pharmaceutical compositions of theinvention may take the form of a pharmaceutical composition as describedbelow.

Exemplary compositions for oral administration include suspensions whichcan contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which can contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate, calcium sulfate, sorbitol, glucose and/or lactoseand/or other excipients, binders, extenders, disintegrants, diluents andlubricants such as those known in the art. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Disintegrators include without limitation starch,methylcellulose, agar, bentonite, xanthan gum and the like. Thecompounds of formula (I) can also be delivered through the oral cavityby sublingual and/or buccal administration. Molded tablets, compressedtablets or freeze-dried tablets are exemplary forms which may be used.Exemplary compositions include those formulating the present compound(s)with fast dissolving diluents such as mannitol, lactose, sucrose and/orcyclodextrins. Also included in such compositions may be high molecularweight excipients such as celluloses (avicel) or polyethylene glycols(PEG). Such compositions can also include an excipient to aid mucosaladhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methylcellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleicanhydride copolymer (e.g., Gantrez), and agents to control release suchas polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use. Lubricants used in these dosage forms includesodium oleate, sodium stearate, magnesium stearate, sodium benzoate,sodium acetate, sodium chloride and the like. For oral administration inliquid form, the oral drug components can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water, and the like.

Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets, pills ortablets each containing a predetermined amount of the active ingredient;as a powder or granules; as a solution or a suspension in an aqueousliquid or a non-aqueous liquid, for example as elixirs, tinctures,suspensions or syrups; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also bepresented as a bolus, electuary or paste.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared bycompressing in a suitable machine the active ingredient in afree-flowing form such as a powder or granules, optionally mixed with abinder, lubricant, inert diluent, lubricating, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets may optionally be coated or scored and maybe formulated so as to provide slow or controlled release of the activeingredient therein. The present compounds can, for example, beadministered in a form suitable for immediate release or extendedrelease. Immediate release or extended release can be achieved by theuse of suitable pharmaceutical compositions comprising the presentcompounds, or, particularly in the case of extended release, by the useof devices such as subcutaneous implants or osmotic pumps. The presentcompounds can also be administered liposomally.

Typical unit dosage compositions are those containing an effective dose,as hereinbefore recited, or an appropriate fraction thereof, of theactive ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions of this invention may include otheragents conventional in the art having regard to the type of compositionin question, for example those suitable for oral administration mayinclude flavoring agents.

The compositions may be presented in unit dosage form and may beprepared by any of the methods well known in the art of pharmacy.Methods may include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. Compositions may be prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both and then, if necessary, shapingthe product into the desired composition.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids,1,2-dipalmitoylphosphatidylcholine, phosphatidyl ethanolamine(cephaline), phosphatidylserine, phosphatidylinositol,diphosphatidylglycerol (cardiolipin) or phosphatidylcholine (lecithin).

Compositions for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the composition isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The compositions may be presented in unit-dose or multi-dosecontainers, for example sealed ampoules and vials, and may be stored ina freeze-dried (lyophilised) condition requiring only the addition ofthe sterile liquid carrier, for example saline or water-for-injection,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described. Exemplary compositions for parenteraladministration include injectable solutions or suspensions which cancontain, for example, suitable non-toxic, parenterally acceptablediluents or solvents, such as polyethylene glycol, ethanol,1,3-butanediol, water, Ringer's solution, an isotonic sodium chloridesolution, or other suitable dispersing or wetting and suspending agents,including synthetic mono- or diglycerides, and fatty acids, includingoleic acid, or Cremaphor.

Exemplary compositions for nasal, aerosol or inhalation administrationinclude solutions in saline, which can contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Compositions for rectal administration may be presented as a suppositorywith the usual carriers such as cocoa butter, synthetic glyceride estersor polyethylene glycol. Such carriers are typically solid at ordinarytemperatures, but liquefy and/or dissolve in the rectal cavity torelease the drug.

Compositions for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerine or sucrose and acacia. Exemplary compositions fortopical administration include a topical carrier such as Plastibase(mineral oil gelled with polyethylene).

Compounds of formula (I) may be administered as the sole pharmaceuticalagent or in combination with one or more additional therapeutic agentswhere the combination causes no unacceptable adverse effects. Thispharmaceutical composition includes administration of a singlepharmaceutical dosage composition which contains a compound of formula(I) and one or more additional therapeutic agents, as well asadministration of the compound of formula (I) and each additionaltherapeutic agent in its own separate pharmaceutical dosage composition.For example, a compound of formula (I) and a therapeutic agent may beadministered to the patient together in a single oral dosage compositionsuch as a capsule or tablet, or each agent may be administered incompositions with separate dosage.

Where separate dosage compositions are used, the compound of formula (I)and one or more additional therapeutic agents may be administered atessentially the same time (e.g., concurrently) or at separatelystaggered times (e.g., sequentially).

The amount of active ingredient which is required to achieve atherapeutic effect will, of course, vary with the particular compound,the route of administration, the subject under treatment, including thetype, species, age, weight, sex, and medical condition of the subjectand the renal and hepatic function of the subject, and the particulardisorder or disease being treated, as well as its severity. Anordinarily skilled physician, veterinarian or clinician can readilydetermine and prescribe the effective amount of the drug required toprevent, counter or arrest the progress of the condition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of bodyweight per day (mg/kg/day) to 10 mg/kg/day, and most preferably 0.1 to5.0 mg/kg/day, for adult humans. For oral administration, thecompositions may be provided in the form of tablets or other forms ofpresentation provided in discrete units containing 0.01, 0.05, 0.1, 0.5,1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, and 500 milligrams of theactive ingredient for the symptomatic adjustment of the dosage to thepatient to be treated. A medicament typically contains from about 0.01mg to about 500 mg of the active ingredient, preferably from about 1 mgto about 100 mg of active ingredient. Intravenously, the most preferreddoses will range from about 0.1 to about 10 mg/kg/minute during aconstant rate infusion. Compounds of the present invention may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three or four times daily.Furthermore, compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wellknown to those of ordinary skill in the art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittent throughout the dosageregimen.

Preparation of Compounds

The compounds in the present invention can be prepared as a free base ora pharmaceutically acceptable salt thereof by the process describedbelow. Throughout the following description of such processes it isunderstood that, where appropriate, suitable protecting groups will beadded to, and subsequently removed from the various reactants andintermediates in a manner that will be readily understood by one skilledin the art of organic synthesis. Conventional procedures for using suchprotecting groups as well as examples of suitable protecting groups arefor example described in Protective Groups in Organic Synthesis by T. W.Greene, P. G. M Wutz, 4^(th) Edition, Wiley-Interscience, New York,2006. It is understood that microwaves can alternatively be used for theheating of reaction mixtures.

Another aspect of the present invention provides a process for preparinga compound of formula (I), or a pharmaceutically acceptable saltthereof, wherein R¹, R² and A are, unless specified otherwise, asdefined herein. Said process comprises of:

(i) Formation of a Corresponding Compound of Formula (I)

A compound of formula (I) may be obtained (Scheme 1) by starting from,for example, a compound of formula (II), wherein R^(X) may be F, OCH₃,OC(CH₃)₃, or OSiR′R″R″′ (wherein R′, R″ and R″′ are independently aryl(such as phenyl) or alkyl (such as methyl or tert-butyl)). If R^(X) is Fthe conversion into (I) may be carried out by for instance acidichydrolysis using aqueous HCl. If R^(X) is OCH₃ the conversion into (I)may be carried out by reaction with for instance trimethylsilyl iodidein a suitable solvent such as chloroform or by reaction with HBr in asuitable solvent such as acetic acid or by reaction with BBr₃ in asuitable solvent such as dichloromethane. If R^(X) is OC(CH₃)₃ theconversion into (I) may be carried out by reaction with for instancetrifluoroacetic acid in a suitable solvent such as dichloromethane. IfR^(X) is OSiR′R″R″′ the conversion into (I) may be carried out by forinstance HCl in a suitable solvent such as methanol or by usingtetrabutyl ammonium fluoride in tetrahydrofuran. If enantiomericallypure or enriched compound (II) is used in this reaction, anenantiomerically pure or enantiomerically enriched compound (I) isobtained.

Compounds of formula (II) are commercially available compounds, or areknown in the literature, or they are prepared by standard processesknown in the art. A compound of formula (I) or (II) may be separatedinto its enantiomers by standard processes known in the art by forexample chromatography on a chiral stationary phase.

General Methods

All solvents used were of analytical grade and commercially availableanhydrous solvents were routinely used for reactions. Starting materialswere available from commercial sources, or prepared according toliterature procedures. Room temperature refers to +20-25° C. Solventmixture compositions are given as volume percentages or volume ratios.

Microwave heating was performed in a Biotage Initiator microwave cavityproducing continuous irradiation at 2.45 GHz. It is understood thatmicrowaves may be used for the heating of reaction mixtures.

Straight phase chromatography was manually performed on Merck Silica gel60 (0.040-0.063 mm), or automatically using an ISCO Combiflash®Companion™ system using SiliaSep™ normal-phase flash columns using thesolvent system indicated.

NMR spectra were recorded on a 400 MHz (or higher field) NMRspectrometer fitted with a probe of suitable configuration. Spectra wererecorded at ambient temperature unless otherwise stated. Chemical shiftsare given in ppm down- and upfield from TMS (0.00 ppm). The followingreference signals were used: the residual solvent signal of DMSO-d₆ δ2.5, CDCl₃ δ 7.26 or Methanol-d₄ δ 3.31. Resonance multiplicities aredenoted s, d, t, q, m and br for singlet, doublet, triplet, quartet,multiplet and broad, respectively.

High pressure liquid chromatography (HPLC) was performed on a reversephase column. A linear gradient was applied using for example mobilephase A (aqueous 0.1% NH₃ or aqueous 0.1% acetic acid or aqueous 0.1%formic acid) and B (acetonitrile or methanol). Mass spectrometer (MS)analyses were performed in positive ion mode using electrosprayionization (ES+).

Preparative chromatography was run on a Gilson-PREP GX271 or GX281 withTrilution Ic as software on a reverse phase column. A linear gradientwas applied using for example mobile phase A (aqueous 0.1% NH₃ oraqueous 0.1% acetic acid or aqueous 0.1% formic acid) and B(acetonitrile or methanol).

Preparative chiral chromatography for separation of enantiomers was runon a Thar SFC using supercritical fluid chromatography on a chiralstationary phase. A linear gradient was applied using mobile phase A(carbon dioxide) and B (acetonitrile or methanol or ethanol or2-propanol or any mixtures thereof). Additives (such as diethyl amine orisopropyl amine or ammonia or formic acid or TFA) may be used.

Compounds have been named using BIOVIA Draw 16.1.

Abbreviations

Amphos (4-(N,N-Dimethylamino)phenyl)di-tert-butyl phosphine

anh. anhydrous

aq. aqueous

BuLi butyl lithium

DCM dichloromethane

DMAc N,N-dimethyl acetamide

DME 1,2-Dimethoxyethane

DMF N,N-dimethyl formamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

EtOH ethanol

h hour(s)

HPLC high pressure (or performance) liquid chromatography

KOtBu potassium tert-butoxide

LCMS liquid chromatography mass spectrometry

MeCN acetonitrile

2-MeTHF 2-methyl tetrahydrofuran

MeOH methanol

min. minute(s)

NMR nuclear magnetic resonance

PEPPSI-iPr[1,3-Bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride

Pd(OAc)₂ palladium(II) acetate

PdCl₂(dppf) [1,1′-Bis(diphenylphosphino)ferrocene] dichloropalladium(II)

quant. quantitative

rt room temperature

sat. saturated

TFA trifluoroacetic acid

THF tetrahydrofuran

EXAMPLE 1 (3R)-4-(2,6-dichloro-4-pyridyl)-3-methyl-morpholine

2,6-Dichloro-4-iodo-pyridine (2 g, 7.3 mmol), (3R)-3-methylmorpholinehydrochloride (1.1 g, 7.99 mmol), PPh₃ (120 mg, 0.46 mmol), Pd(OAc)₂ (50mg, 0.22 mmol) and freshly ground K₃PO₄ (5.5 g, 25.9 mmol) were taken upin DMF (15 ml). The resulting mixture was degassed with nitrogen for 5min and stirred at 100° C. overnight. When cooled to rt the mixture waspoured into water (50 ml) and EtOAc (15 ml). The organic layer wasseparated and the aqueous layer was extracted with EtOAc (3×10 ml). Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,concentrated and purified on a silica gel column eluted with 10-60%EtOAc in heptane to give the product as a solid (520 mg, 29%). MS ES+m/z 247 [M+H]⁺.

EXAMPLE 2 (3R)-4-(2-tert-butoxy-6-chloro-4-pyridyI)-3-methyl-morpholine

(3R)-4-(2,6-dichloro-4-pyridyl)-3-methyl-morpholine (520 mg, 2.1 mmol),KOtBu (500 mg, 4.46 mmol) and 4A molecular sieves (˜10 beads, 4-8 mesh)were taken up in toluene (8 ml) and stirred at 90° C. for 2 h. Whencooled to rt the mixture was diluted with EtOAc (10 ml), brine (5 ml)and water (5 ml). The organic layer was separated and the aqueous layerextracted with EtOAc (10 ml). The combined organics were washed withbrine, concentrated and purified on a silica gel column eluted with0-40% EtOAc in heptane to give the product as an oil. MS ES+ m/z 285[M+H]⁺.

EXAMPLE 3 tert-Butyl4-[6-tert-butoxy-4-[(3R)-3-methylmorpholin-4-yl]-2-pyridyl]-3-(trifluoromethyl)piperazine-1-carboxylate

A mixture of tert-butyl 3-(trifluoromethyl)piperazine-1-carboxylate (500mg, 1.97 mmol),(3R)-4-(2-tert-butoxy-6-chloro-4-pyridyl)-3-methyl-morpholine (670 mg,2.36 mmol), KOtBu (440 mg, 3.94 mmol) and PEPPSI-Ipr (133 mg, 0.2 mmol)in 1,4-dioxane (15 ml) was heated in a microwave reactor at 130° C. for3 h. The reaction mixture was poured into water (10 ml) and extractedwith EtOAc (3×20 ml). The combined organics were washed with brine,dried over Na₂SO₄, filtered, concentrated and purified on a silica gelcolumn eluted with 20-30% EtOAc in heptane to give the product as an oil(420 mg, 42%). MS ES+ m/z 503 [M+H]⁺.

EXAMPLE 4(3R)-4-[2-tert-butoxy-6-[2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

LiAlH₄ (63 mg, 1.67 mmol) was added at 0° C. to a solution of tert-butyl4-[6-tert-butoxy-4-[(3R)-3-methyl morpholin-4-yl]-2-pyridyl]-3-(trifluoromethyl)piperazine-1-carboxylate (420 mg,0.84 mmol) in THF (10 ml) and the resulting mixture was stirred at rtfor 5 h. The reaction mixture was quenched with ice/water and extractedwith EtOAc (3×10 ml). The combined organics were washed with brine,dried over Na₂SO₄, filtered, concentrated and purified on a silica gelcolumn eluted with 4-5% MeOH in DCM to give the product as a solid (200mg, 59%). MS ES+ m/z 403 [M+H]⁺.

EXAMPLE 5(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

Methanesulfonyl chloride (85 mg, 0.75 mmol) was added drop wise to asolution of(3R)-4-[2-tert-butoxy-6-[2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine(200 mg, 0.5 mmol) and Et₃N (100 mg, 0.99 mmol) in DCM (15 ml) at 0° C.and the resulting mixture was stirred at rt for 3 h. The reactionmixture was quenched with ice/water and extracted with EtOAc (3×10 mL).The combined organics were washed with brine, dried over Na₂SO₄,filtered, concentrated and purified on a silica gel column eluted with0-100% EtOAc in heptane to give the product as a solid (150 mg, 63%). MSES+ m/z 481 [M+H]⁺.

EXAMPLE 6 (R) and (S)4-[(3R)-3-methylmorpholin-4-yl]-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one

TFA (0.4 ml, 5.23 mmol) was added to a solution of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine(150 mg, 0.31 mmol) in DCM (15 ml) at 0° C. and the resulting mixturewas stirred at rt for 6 h. The pH was adjusted above 7 using sat. aq.NaHCO₃ and the mixture extracted with DCM (3×10 ml). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered,concentrated and purified on a silica gel column eluted with 0-10% MeOHin DCM to give the product as a solid (20 mg, 23%).

Chiral separation by SFC gave the two isomers.

EXAMPLE 6-1 First Isomer to Elute, with Unknown Absolute Configuration

¹H NMR (400 MHz, DMSO-d₆): δ 10.45 br·s., 1H), 5.75 (br·s., 1H), 5.56(br·S., 1H), 5.43 (br·s., 1H), 4.09 (br·s., 1H), 3.90-3.69 (m, 3H),3.66-3.35 (m, 2H), 3.51-3.39 (m 3H), 3.21-3.10 (m, 1H), 3.10-3.08 (m,1H), 3.02-2.69 (m, 1H), 2.95-2.91 (s, 3H), 2.84-2.79 (m, 1H), 1.06-1.05(m, 3H). MS ES+ m/z 425 [M+H]⁺.

EXAMPLE 6-2 Second Isomer to Elute, with Unknown Absolute Configuration

¹H NMR (400 MHz, DMSO-d₆): δ 10.45 (br·s., 1H), 5.76 (br·s., 1H), 5.56(br·s., 1H), 5.43 (br·s., 1H), 4.09 (br·s.,1H), 3.90-3.69 (m, 3H),3.66-3.35 (m, 2H), 3.51-3.39 (m 3H), 3.21-3.10 (m, 1H), 3.10-3.08 (m,1H), 3.02-2.69 (m, 1H), 2.95-2.91 (s, 3H), 2.84-2.79 (m, 1H), 1.06-1.05(m,3H). MS ES+ m/z 425 [M+H]⁺.

EXAMPLE 7(3R)-4-[2-tert-butoxy-6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, using(4-fluorophenyl)methanesulfonyl chloride instead of methanesulfonylchloride, to give the product as a solid (40 mg, 37%). MS ES+ m/z 575[M+H]⁺.

EXAMPLE 86-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6 using(3R)-4-[2-tert-butoxy-6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholineinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (12 mg, 33%). ¹H NMR (400 MHz, DMSO-d₆):δ 7.4 (q, 2H), 7.2 (t, 2H), 5.7 (br·s., 1H), 5.43 (br·s., 1H), 4.5(br·s., 2H), 4.09(t, 1H), 3.90 (t, 2H), 3.8 (d, 1H), 3.6 (q, 3H), 3.4(m,3H), 3.08 (m, 3H), 2.8 (t, 1H), 1.06-1.05 (t, 3H). MS ES+ m/z 519[M+H]⁺.

EXAMPLE 9(3R)-4-[2-tert-butoxy-6-[4-[(5-fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, using5-fluoropyridine-3-sulfonyl chloride instead of methanesulfonylchloride, to give the product as a solid (40 mg, 32%). MS ES+ m/z 562[M+H]⁺.

EXAMPLE 106-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6 using(3R)-4-[2-tert-butoxy-6-[4-[(5-fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholineinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (26 mg, 72%). ¹H NMR (400 MHz, DMSO-d₆):δ 9.8 (br·s., 1H), 8.9 (d, 1H), 8.8 (br·s., 1H), 8.2 (d, 1H), 5.7(br·s., 1H), 5.6 (s, 1H), 5.5 (s, 1H), 5.4 (s, 1H), 4.0 (t, 2H), 3.8 (d,2H), 3.7-3.6 (t, 2H), 3.5 (d, 1H), 3.4 (m, 1H), 3.3 (br·s., 1H), 3.2 (d,1H), 2.9(m, 1H), 2.8 (d, 1H), 2.5 (m, 1H), 1.2 (t, 1H), 1.06-1.05 (q,3H). MS ES+ m/z 506 [M+H]⁺.

EXAMPLE 11(3R)-4[2-tert-butoxy-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, usingtetrahydrofuran-3-sulfonyl chloride instead of methanesulfonyl chloride,to give the product as a solid (35 mg, 35%). MS ES+ m/z 537 [M+H]⁺.

EXAMPLE 124-[(3R)-3-methylmorpholin-4-yl]-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6 using(3R)-4-[2-tert-butoxy-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholineinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (26 mg, 83%). ¹H NMR (400 MHz, DMSO-d₆):δ 9.8 (br·s., 1H), 5.7 (d, 1H), 5.5 (d, 1H), 4.0 (m, 2H), 3.9-3.7 (m,6H), 3.6 (m, 4H), 3.5 (m, 3H), 3.0 (m, 2H), 2.4-2.1 (m, 1H), 2.0 (m,1H), 1.9-1.1 (q, 1H), 1.0 (q, 3H). MS ES+ m/z 481 [M+H]⁺.

EXAMPLE 13(3R)-4[2-tert-butoxy-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, usingpyrrolidine-1-sulfonyl chloride instead of methanesulfonyl chloride, togive the product as a solid (76 mg, 71%). MS ES+ m/z 536 [M+H]⁺.

EXAMPLE 144-[(3R)-3-methylmorpholin-4-yl]-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6 using(3R)-4-[2-tert-butoxy-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholineinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (48 mg, 72%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.05-1.12 (m, 3 H), 1.82-1.89 (m, 4 H), 2.85 (br t, 1 H), 3.00 (td,1 H), 3.10 (br d, 1 H), 3.16-3.31 (m, 5 H), 3.33-3.42 (m, 1 H),3.44-3.56 (m, 2 H), 3.59-3.65 (m, 1 H), 3.66-3.71 (m, 1 H), 3.83 (dd, 1H), 3.90 (br dd, 2 H), 4.01 (br s, 1 H), 5.43 (br s, 1 H), 5.49 (br s, 1H), 5.70 (br s, 1 H), 9.81 (br s, 1 H). MS ES+ m/z 480 [M+H]⁺.

EXAMPLE 154-[6-tert-Butoxy-4-[(3R)-3-methylmorpholin-4-yl]-2-pyridyl]-N,N-dimethyl-3-(trifluoromethyl)piperazine-1-sulfonamide

The title compound was prepared as described in Example 5, usingN,N-dimethylsulfamoyl chloride instead of methanesulfonyl chloride, togive the product as a solid (60 mg, 59%). MS ES+ m/z 510 [M+H]⁺.

EXAMPLE 16N,N-dimethyl-4-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide

The title compound was prepared as described in Example 6 using4-[6-tert-Butoxy-4-[(3R)-3-methylmorpholin-4-yl]-2-pyridyl]-N,N-dimethyl-3-(trifluoromethyl)piperazine-1-sulfonamideinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (18 mg, 37%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.05-1.12 (m, 3 H), 2.80 (d, 6 H), 2.86-2.95 (m, 1 H), 3.00 (td, 1H), 3.12-3.24 (m, 2 H), 3.34-3.41 (m, 1 H), 3.44-3.56 (m, 2 H),3.59-3.64 (m, 1 H), 3.66-3.74 (m, 1 H), 3.81-3.95 (m, 3 H), 4.04 (br s,1 H), 5.44 (br s, 1 H), 5.49 (br s, 1 H), 5.70 (br s, 1 H), 9.50-10.12(m, 1 H). MS ES+ m/z 454 [M+H]⁺.

EXAMPLE 17 (3R)-4-[2-tert-butoxy-6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, using2-methoxyethanesulfonyl chloride instead of methanesulfonyl chloride, togive the product as a solid (74 mg, 76%). MS ES+ m/z 525 [M+H]⁺.

EXAMPLE 186-[4-(2-Methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6 using(3R)-4-[2-tert-butoxy-6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholineinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (48 mg, 75%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.05-1.16 (m, 3 H), 2.90 (br t, 1 H), 3.00 (td, 1 H), 3.11-3.23 (m,2 H), 3.25-3.30 (m, 3 H), 3.33-3.51 (m, 4 H), 3.55-3.71 (m, 5 H),3.83-3.96 (m, 3 H), 4.05 (br s, 1 H), 5.44 (br s, 1 H), 5.50 (br s, 1H), 5.72 (br s, 1 H), 9.81 (br s, 1 H). MS ES+ m/z 469 [M+H]⁺.

EXAMPLE 19(3R)-4-[2-tert-butoxy-6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, using4-fluorobenzenesulfonyl chloride instead of Methanesulfonyl chloride, togive the product as a solid (40 mg, 41%). MS ES+ m/z 561 [M+H]⁺.

EXAMPLE 206-[4-(4-Fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6 using(3R)-4-[2-tert-butoxy-6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholineinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (22 mg, 61%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.04 (dd, 3 H), 2.28-2.36 (m, 1 H), 2.53-2.60 (m, 1 H), 2.97 (td, 1H), 3.23 (br t, 1 H), 3.40-3.54 (m, 3 H), 3.55-3.72 (m, 3 H), 3.84-4.01(m, 2 H), 4.56 (t, 1 H), 5.40 (br s, 1 H), 5.49 (br s, 1 H), 5.67 (br s,1 H), 7.47-7.53 (m, 2 H), 7.86 (dd, 2 H), 9.78 (br s, 1 H). MS ES+ m/z505 [M+H]⁺.

EXAMPLE 21(3R)-4-[2-tert-butoxy-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, using2-methylpyrazole-3-sulfonyl chloride instead of methanesulfonylchloride, to give the product as a solid (90 mg, 82%). MS ES+ m/z 547[M+H]⁺.

EXAMPLE 224-[(3R)-3-methylmorpholin-4-yl]-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6 using(3R)-4-[2-tert-butoxy-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholineinstead of(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine,to give the product as a solid (35 mg, 54%). ¹H NMR (500 MHz, DMSO-d₆) δppm 1.06 (dd, 3 H), 2.64-2.74 (m, 1 H), 2.92-3.03 (m, 2 H), 3.20-3.30(m, 1 H), 3.33-3.52 (m, 2 H), 3.57-3.64 (m, 1 H), 3.65-3.74 (m, 2 H),3.81-3.91 (m, 2 H), 3.93-4.02 (m, 1 H), 4.03-4.06 (m, 3 H), 4.06-4.14(m, 1 H), 5.44 (s, 1 H), 5.55 (br s, 1 H), 5.71 (s, 1 H), 6.92 (dd, 1H), 7.65 (dd, 1 H), 9.82 (br s, 1 H). MS ES+ m/z 491 [M+H]⁺.

EXAMPLE 23(3R)-4-[2-tert-butoxy-6-[4-cyclopropylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, usingcyclopropanesulfonyl chloride, to give the product as a solid (80 mg,79%). MS ES+ m/z 507 [M+H]⁺.

EXAMPLE 246-[4-Cyclopropylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6, to give theproduct as a solid (42 mg, 59%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm0.93-1.09 (m, 7 H), 2.53-2.65 (m, 1 H), 2.90-3.05 (m, 2 H), 3.16-3.24(m, 2 H), 3.33-3.52 (m, 2 H), 3.56-3.64 (m, 2 H), 3.65-3.72 (m, 1 H),3.85-3.96 (m, 3 H), 4.10 (br s, 1 H), 5.44 (br s, 1 H), 5.56 (br d, 1H), 5.76 (s, 1 H), 9.77 (br s, 1 H). MS ES+ m/z 451 [M+H]⁺.

EXAMPLE 25(3R)-4-[2-tert-butoxy-6-[4-(1-piperidylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, usingpiperidine-1-sulfonyl chloride, to give the product as a solid (100 mg,92%). MS ES+ m/z 550 [M+H]⁺.

EXAMPLE 264-[(3R)-3-methylmorpholin-4-yl]-6-[4-(1-piperidylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6, to give theproduct as a solid (42 mg, 47%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.07(dd, 3 H), 1.52 (br s, 6 H), 2.85-3.03 (m, 1 H), 3.08-3.12 (m, 1 H),3.17 (br d, 5 H), 3.34-3.39 (m, 1 H), 3.45 (br s, 1 H), 3.47-3.52 (m, 2H), 3.61 (dt, 1 H), 3.69 (dd, 1 H), 3.80 (d, 1 H), 3.83 (d, 1 H),3.88-3.93 (m, 2 H) , 5.43 (s, 1 H), 5.48 (br s, 1 H), 5.70 (s, 1 H),9.32-9.88 (m, 1 H). MS ES+ m/z 494 [M+H]⁺.

EXAMPLE 27(3R)-4-[2-tert-butoxy-6-[4-morpholinosulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, usingmorpholine-4-sulfonyl chloride, to give the product as a solid (75 mg,77%). MS ES+ m/z 483 [M+H]⁺.

EXAMPLE 284-[(3R)-3-methylmorpholin-4-yl]-6-[4-morpholinosulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6, to give theproduct as a solid (16 mg, 64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.07(dd, 3 H), 2.88-3.08 (m, 2 H), 3.12-3.23 (m, 6 H), 3.36-3.41 (m, 1 H),3.43-3.50 (m, 1 H), 3.52-3.70 (m, 7 H), 3.82-3.96 (m, 3 H), 4.02 (br s,1 H), 5.44 (br s, 1 H), 5.49 (br s, 1 H), 5.71 (br s, 1 H), 9.84 (br s,1 H). MS ES+ m/z 496 [M+H]⁺.

EXAMPLE 29(3R)-4-[2-tert-butoxy-6-[4-(1,2-dimethylimidazol-4-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine

The title compound was prepared as described in Example 5, using1,2-dimethylimidazole-4-sulfonyl chloride, to give the product as asolid (120 mg, 86%). MS ES+ m/z 561 [M+H]⁺.

EXAMPLE 306-[4-(1,2-Dimethylimidazol-4-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6, to give theproduct as a solid (24 mg, 23%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.04-1.09 (m, 3 H), 2.25-2.32 (m, 3 H), 2.41-2.49 (m, 1 H), 2.65-2.82(m, 1 H), 2.91-3.06 (m, 1 H), 3.09-3.29 (m, 1 H), 3.29-3.49 (m, 3 H),3.59-3.62 (m, 1 H), 3.64-3.71 (m, 1 H), 3.82-3.94 (m, 4 H), 4.08 (br d,1 H), 4.56-4.58 (m, 1 H), 5.41 (s, 1 H), 5.47 (br d, 1 H), 5.64-5.73 (m,1 H), 7.62-7.84 (m, 1 H), 7.80 (s, 1 H), 10.45 (m, 1 H). MS ES+ m/z 505[M+H]⁺.

EXAMPLE 316-[4-(1-methylcyclopropyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one

To an ice cooled solution of(3R)-4-[2-tert-butoxy-6-[2-(trifluoromethyl)piperazin-1-yl]-4-pyridyl]-3-methyl-morpholine(70 mg, 0.17 mmol in DCM (5 ml) was added TEA (0.12 ml, 0.87 mmol) and1-methylcyclopropanesulfonyl chloride (40 mg, 0.26 mmol). The coolingbath was removed, and the resulting mixture was stirred at rt overnight.More 1-methylcyclopropanesulfonyl chloride (40 mg, 0.26 mmol) was addedand the reaction was stirred at rt for 20 h. More1-methylcyclopropanesulfonyl chloride (40 mg, 0.26 mmol) was added andthe reaction was kept at rt for 2 months. The resulting residue waspurified by preparative HPLC to give the product as a solid (21 mg,26%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.80-0.90 (m, 2 H), 1.06-1.07 (m ,3 H) 1.12-1.28 (m, 2 H), 1.41 (s, 3 H), 2.94-3.10 (m, 2 H), 3.12-3.24(m, 1 H), 3.28-3.31 (m, 1 H), 3.35-3.41 (m, 1 H), 3.42-3.51 (m, 1 H),3.58-3.73 (m, 3 H), 3.87-4.00 (m, 3 H), 4.03 (br d, 1 H), 5.44 (br s, 1H), 5.48 (br s, 1 H), 5.71 (s, 1 H), 9.86 (br s, 1 H). MS ES+ m/z 465[M+H]⁺.

EXAMPLE 32(3R)-4-[2-tert-butoxy-6-[4-methylsulfonyl-2-(trifluoromethyl)phenyl]-4-pyridyl]-3-methyl-morpholine

(3R)-4-(2-tert-butoxy-6-chloro-4-pyridyl)-3-methyl-morpholine (85 mg,0.3 mmol), K₂CO₃ (83 mg, 0.6 mmol),[4-methylsulfonyl-2-(trifluoromethyl)phenyl]boronic acid (80 mg, 0.3mmol) and PdCl₂(Amphos) (11 mg, 0.02 mmol) were taken up in 1,4-dioxane(2 ml) and water (0.6 ml) and the resulting mixture was stirred at 95°C. for 1 h. The reaction allowed to cool and[4-methylsulfonyl-2-(trifluoromethyl)phenyl]boronic acid (161 mg, 0.6mmol) and PdCl₂(Amphos) (11 mg, 0.02 mmol) were added and the reactionwas heated again and stirred at 95° C. for 3 h. When cooled to rt themixture was extracted with EtOAc and the combined organics were washedwith brine, dried over Na₂SO₄, filtered, concentrated and purified on asilica gel column eluted with 0-50% EtOAc in heptane to give the productas a solid (22 mg, 16%). MS ES+ m/z 473 [M+H]⁺.

EXAMPLE 334-[(3R)-3-methylmorpholin-4-yl]-6-[4-methylsulfonyl-2-(trifluoromethyl)phenyl]-1H-pyridin-2-one

The title compound was prepared as described in Example 6, to give theproduct as a solid (8 mg, 47%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (d,3 H), 3.03 (td, 1 H), 3.30-3.39 (m, 1 H), 3.33-3.41 (m, 3 H), 3.43-3.54(m, 1 H), 3.58-3.70 (m, 2 H), 3.86-3.95 (m, 2 H), 5.48 (br s, 1 H), 6.08(br s, 1 H), 7.87 (d, 1 H), 8.28-8.33 (m, 2 H), 11.07 (br s, 1 H). MSES+ m/z 417 [M+H]⁺.

EXAMPLE 344-[6-tert-Butoxy-4-[(3R)-3-methylmorpholin-4-yl]-2-pyridyl]-N,N-dimethyl-3-(trifluoromethyl)benzenesulfonamide

A mixture of 4-bromo-N,N-dimethyl-3-(trifluoromethyl)benzenesulfonamide(199 mg, 0.6 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(183 mg, 0.72 mmol), KOAc (118 mg, 1.2 mmol) and PdCl₂(dppf) (44 mg,0.06 mmol) in DMSO (2.5 ml) was stirred at 90° C. overnight. When cooledto rt, (3R)-4-(2-tert-butoxy-6-chloro-4-pyridyl)-3-methyl-morpholine(171 mg, 0.6 mmol), K₂CO₃ (166 mg, 1.20 mmol), PdCl2(dppf) (22 mg, 0.03mmol), 1,4-dioxane (1 ml) and water (1 ml) were added and the reactionwas stirred at 85° C. for 2 h . When cooled to rt,[4-(dimethylsulfamoyl)-2-(trifluoromethyl)phenyl]boronic acid (178 mg,0.6 mmol), K₂CO₃ (83 mg, 0.6 mmol) and PdCl₂(dppf) (22 mg, 0.03 mmol)were added and the reaction was stirred at 85° C. for 5 h. The reactionwas added to water and extracted with EtOAc. The combined organics werewashed with brine, dried over Na₂SO₄, filtered, concentrated andpurified on a silica gel column eluted with 0-80% EtOAc in heptane togive the product as a solid (200 mg, 67%). MS ES+ m/z 502 [M+H]⁺.

EXAMPLE 35N,N-dimethyl-4-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)benzenesulfonamide

The title compound was prepared as described in Example 6. When thereaction was complete the mixture was concentrated, chased with tolueneand purified by preparative HPLC to give the product as a solid (85 mg,50%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.10 (d, 3 H), 2.66-2.78 (m, 6 H),3.03 (td, 1 H), 3.38 (br s, 1 H), 3.48 (td, 1 H), 3.57-3.70 (m, 2 H),3.87-3.96 (m, 2 H), 5.48 (br s, 1 H), 6.12 (br s, 1 H), 7.86 (d, 1 H),8.03 (d, 1 H), 8.12 (dd, 1 H), 11.02 (br s, 1 H). MS ES+ m/z 446 [M+H]⁺.

EXAMPLE 36 Vps34 Biochemical Assay

Dilution series of compounds of the invention were prepared in DMSO at100 times the final assay concentration (n₁=n₀/3 in 10 points). Thecompounds were further diluted to 4 times the assay concentration inassay buffer (Life technologies buffer Q, PV5125, diluted 5 timessupplemented with 2 mM DTT and 2 mM MnCl₂). 2.5 μl of the dilutedcompounds were added to a 384 well assay plate followed by 2.5 μl of16.5 nM Vps34 enzyme (Life technologies, PV5126). Enzyme and compoundswere pre-incubated at rt for 15 min. Then 5 μl of substrate mixcontaining 20 μM ATP (Life technologies, PV3227) and 200 μM PI:PSsubstrate (Life technologies, PV5122) in assay buffer was added to thewells containing compound and enzyme. Mixing was performed by pipettingseveral times. The reaction was incubated at room temperature for 1 h.Then 5 μl stop-detection mix, prepared as described in the Adapta kinaseassay kit instructions (Life technologies, PV5099) containing AdaptaEu-anti-ADP antibody (2.3 nM), Alexa Fluor 647 ADP tracer (9 nM) andEDTA (30 mM) in TR-FRET buffer, was added to quench the reaction. Mixingwas performed by pipetting several times. The assay plate was thenincubated at room temperature for 30 min and read with Artemis microplate reader. Percent inhibition of the compounds as compared to DMSOtreated control samples was calculated. By the use of Dotmatics softwarecompound concentration versus percent inhibition was fitted to generateIC₅₀ values. The example compounds effectively inhibited Vps34 and theresults of the assay are shown in Table 1 (Median IC₅₀ nM Adapta).

TABLE 1 Median IC₅₀ values for the Vps34 assay Example Compound MedianIC₅₀ nM Adapta 6-1 <5 6-2 15 12 <5 10 <5  8 <5 16 <5 14 <5 18 <5 20 <522 <5 24 <5 26 <5 28 <5 30 <5 31 <5 33 <5 35 <5

EXAMPLE 37 High Content Screening Autophagy Assay

Human osteosarcoma cells (HOS) stably expressing a Green FluorescentProtein (GFP) tagged LC₃ (GFP-LC₃) were used to determine the inhibitoryeffect on autophagy of proprietary compounds. For that purpose,autophagy was activated by using the mTOR inhibitor KU-0063794 at 500 nMin the presence of Bafilomycin A1 (Sigma-Aldrich) at 5 nM. Shortly,cells were plated overnight in clear bottom 96-well plates in DMEM-HighModified media (Hi-Clone Cat # SH30285.01). At the start of theexperiment, the media was removed and replaced with fresh mediacontaining the mTOR inhibitor, Bafilomycin A1 and the vehicle or a testcompound as indicated. After 6 hours the media was removed, cells werewashed twice with ice-cold phosphate buffered saline (PBS) and fixedwith 4% paraformaldehyde for 20 minutes at room temperature. Then thecells were washed twice with ice-cold PBS before adding Hoechst 33342 at1 μg/ml in PBS for nuclear staining. After incubation overnight at 4°C., cells were washed once with PBS to remove the excess of dye and 100μl of PBS was added to each well. Images were acquired at 20×magnification, 6 images per well, using the ImageXpress automatedmicroscope (Molecular Devices Inc.) and analyzed with MetaXpresssoftware to identify LC₃-GFP foci. Foci area per cell values were usedto generate dose response curves and IC₅₀ values were calculated usingthe non-linear fitting analysis in GraphPad Prism software. The testedexample compounds effectively inhibited autophagy in HOS cells. Theresults of the assay are shown in Table 2 (Median IC₅₀ nM HOS-LC₃).

TABLE 2 Median IC₅₀ values for the Vps34 assay and autophagy in HOScells assay. Example Median IC₅₀ nM Compound Cellular assay 6-1 33 12 5510 106  8 12 16 17 18 83 20 223 22 95 24 28 26 139 28 248 30 84 33 49135 458

1. A compound of formula (I)

wherein R¹ is C₁-C₃alkyl or cyclopropyl; R² is selected from hydrogen,C₁-C₃haloalkyl and C₁-C₃alkyl; A is

wherein R³ is selected from R⁶, C₁-C₆alkyl, amino, N—C₁-C₃alkylamino,N,N-diC₁-C₃alkylamino and C₁-C₃alkoxyC₁-C₃alkyl, said C₁-C₆alkyl andsaid C₁-C₃alkoxyC₁-C₃alkyl being optionally substituted with one R⁶and/or one or more halo; R⁴ is selected from C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl, C₃-C₆cycloalkyl and phenyl, said phenyl being optionallyand independently substituted with one of more of fluoro, chloro,methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl,cyclopropyl; R⁵ is selected from halogen, C₁-C₆alkyl, C₁-C₆alkoxy,C₁-C₆haloalkyl and C₃-C₆cycloalkyl; R⁶ is selected from phenyl,monocyclic heteroaryl, C₃-C₆cycloalkyl, heterocyclyl, each optionallysubstituted with one or more R⁷; R⁷ is selected from halogen, amino,N-C₁-C₃alkylamino, N,N-diC₁-C₃alkylamino, C₁-C₃alkoxyC₁-C₃alkyl,C₁-C₃alkoxy, C₁-C₃haloalkoxy, C₃-C₆cycloalkyl, C₁-C₃haloalkyl andC₁-C₃alkyl; or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein R² is selected from hydrogen andC₁-C₃alkyl, or a pharmaceutically acceptable salt thereof.
 3. (canceled)4. The compound according to claim 1, wherein R⁷ is selected fromfluoro, cyclopropyl and methyl, or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 1, wherein R⁴ is selectedfrom methyl, trifluoromethyl, cyclopropyl and phenyl, said phenyl beingoptionally meta-substituted with one of fluoro, chloro, methyl, methoxy,dimethylamino, trifluoromethoxy, trifluoromethyl and cyclopropyl; and R⁵is selected from chloro, cyclopropyl, methyl and trifluoromethyl, or apharmaceutically acceptable salt thereof.
 6. The compound according toclaim 1, wherein R⁴ is selected from methyl, trifluoromethyl andcyclopropyl; and R⁵ is selected from chloro, cyclopropyl, methyl andtrifluoromethyl, or a pharmaceutically acceptable salt thereof. 7.(canceled)
 8. The compound according to claim 1, wherein R³ is selectedfrom R⁶, C₁-C₃alkyl, N,N-diC₁-C₃alkylamino and methoxyC₁-C₃alkyl, saidC₁-C₃alkyl being optionally substituted with one R⁶, or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1, wherein R⁶ is selected from phenyl, pyridyl, morpholinyl,imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, cyclopropyl, cyclopentyl,pyrrolidinyl and tetrahydrofuryl, each optionally substituted with oneor more R⁷, or a pharmaceutically acceptable salt thereof.
 10. Thecompound according to claim 1, wherein R⁶ is selected from phenyl,pyridyl, morpholinyl, imidazolyl, pyrazolyl, cyclopropyl, pyrrolidinyl,piperidinyl, and tetrahydrofuryl, each optionally substituted with oneor more R⁷, or a pharmaceutically acceptable salt thereof. 11.(canceled)
 12. The compound according to claim 1, wherein R⁶ is selectedfrom

or a pharmaceutically acceptable salt thereof. 13-14. (canceled)
 15. Thecompound according to claim 1, wherein R³ is selected from

or a pharmaceutically acceptable salt thereof. 16-19. (canceled)
 20. Thecompound according to claim 1, wherein R¹ is methyl or cyclopropyl; R²is hydrogen; A is

and R³ is selected from

or a pharmaceutically acceptable salt thereof.
 21. The compoundaccording to claim 1, wherein R¹ is methyl; R² is hydrogen; R⁴ and R⁵are CF₃; A is

and R³ is selected from

or a pharmaceutically acceptable salt thereof.
 22. The compoundaccording to claim 1, wherein R¹ is methyl; R² is hydrogen; R⁴ is CF₃; Ais

and R³ is selected from

or a pharmaceutically acceptable salt thereof.
 23. The compoundaccording to claim 1, wherein R¹ is methyl or cyclopropyl; R² ishydrogen; R⁴ and R⁵ are CF₃; A is

and R³ is selected from

or a pharmaceutically acceptable salt thereof.
 24. The compoundaccording to claim 1, said compound being4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide;6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;6-[4-Cyclopropylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;4-(3-methylmorpholin-4-yl)-6-[4-(1-piperidylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;4-(3-methylmorpholin-4-yl)-6-[4-morpholinosulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one;6-[4-(1,2-Dimethylimidazol-4-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;6-[4-(1-methylcyclopropyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one;4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)phenyl]-1H-pyridin-2-one;andN,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)benzenesulfonamide,or a pharmaceutically acceptable salt thereof. 25-36. (canceled)
 37. Amethod of treating cancer, comprising administering a therapeuticallyeffective amount of a compound according to claim 1, or apharmaceutically acceptable salt thereof, to a patient in need thereof.38. The method of claim 37, wherein said cancer is selected breastcancer, such as triple negative breast cancer, bladder cancer, livercancer, cervical cancer, pancreatic cancer, leukemia, lymphoma, renalcancer, colon cancer, glioma, prostate cancer, ovarian cancer, melanomaand lung cancer, as well as hypoxic tumors.
 39. The method of claim 37in conjunction with radiation therapy. 40-42. (canceled)
 43. Apharmaceutical composition comprising a compound according to claim 1,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable diluent, carrier and/or excipient.
 44. A pharmaceuticalcomposition, comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, andanother anticancer agent selected from alkylating agents,antimetabolites, anticancer camptothecin derivatives, plant-derivedanticancer agents, antibiotics, enzymes, platinum coordinationcomplexes, tyrosine kinase inhibitors, hormones, hormone antagonists,monoclonal antibodies, interferons, and biological response modifiers.